Metabolism and Genome Integrity Flashcards
What are the most common features of accelerated aging?
Disruption in metabolism and genome integrity.
What type of gene is age-1/daf-23 and what affect does it have in C . elegans?
It is a recessive, loss of function gene which limits adult life.
What does a complete loss of function in daf-23/age-1 cause in C. elegans?
Constitutive production of dauerlarvae.
What does partial loss of function of daf-23/age-1 lead to in C. elegans?
Normal adults which live longer. They display some of the long living phenotype of the dauerlarvae without actually becoming one.
What is dauer formation regulated by?
The insulin signalling pathway
What does insulin do?
Promotes glucose uptake from the blood and conversion of glucose to glycogen.
Increased fatty acid synthesis.
Increases esterification of fatty acids.
What two receptors regulate insulin signalling in mammals?
The insulin receptor and the insulin-like growth factor 1 receptor
If calories are restricted, leading to no insulin, will Daf-16 be turned on or off? What is the effect on dauerlarvae development?
Daf-16 is turned on if insulin is low, leading to dauer development
Why is daf-16 required for age-1/daf-23 longevity?
Daf-16 mutants block age-1/daf-23
True or false: The mutant alleles which cause longevity in C. elegans are all partial loss of function.
True
What is the equivalent to Daf-16 in humans?
FOXO (Forkhead transcription factor)
A downstream target of daf-16 are the chaperones. What do these promote?
Proteostasis
What does partial calorific restriction promote in C. elegans?
Longevity
What do mutants which block insulin signalling in C. elegans promote?
Dauerlarvae formation
What do mutants which partially block insulin signalling promote in C. elegans?
Longevity
In what other species do the same genes present in C. elegans promote longevity?
Drosophila - starved flies live longer.
What molecule is known as the “Guardian of the Genome”?
p53
What is the name given to the terminal stress activated defence mechanism which is regulated by p53?
Cellular senescence
What is p53 and what does it regulate?
It is a transcription factor which regulates gene expression.
What percentage of human cancers have a mutation which inactivates p53? Where does this mutation usually occur?
50% of all human cancers have a mutation which inactivates p53. This is usually found in its DNA binding domain.
What is p53’s response to moderate genome damage?
Induces DNA repair allowing for a return to normal.
What is p53’s response to severe genome damage such as telomere dysfunction?
Senescene
What is p53’s response to severe genome damage along with hyperproliferation?
Apoptosis
Name four things which p53 acts in response to
1) DNA damage
2) Telomere dysfunction
3) Oncogene activation
4) Reactive oxygen species
What is cellular senescence?
A stable, and usually irreversible, cell cycle arrest.
What does cellular senescence defend against?
It protects organisms against potentially dangerous cells such as pre-cancerous cells. It has a tumour suppressor function.
What are some triggers of cellular senescence?
Response to DNA damage, telomere loss, loss of nuclear integrity, and other forms of cellular damage.
During aging, what can cellular senescence contribute to?
The depletion of stem cells.
Accumulation of senescent cells is a main hallmark, and possible major cause, of what?
Ageing
What are telomeres?
Repetitive DNA sequences at the end of chromosomes.
Why do the end of chromosomes shorten with every replication cycle?
Telomere repeats are lost as DNA polymerase is incapable of replicating all the way to the end of linear chromosomes.
What happens once all telomere repeats are lost?
The shortening of chromosome ends continues, eventually causing gene deletion.
There is a clear correlation between number of cell culture doublings and what feature of the organism?
Life expectancy
What is the Hayflick limit?
The Hayflick limit, discovered in the 1960s, describes the finite number of times cells can divide in cell culture before they have severe telomere shortening or loss. This is when they become senescent (induced by p53).
What direction does DNA polymerase work and what does it require to initiate polymerisation?
DNA polymerase can only work in the 5’ to 3’ direction and required a primer to initiate polymerisation. It is initiated by RNA primers which then degrade, leaving single stranded DNA.
What does telomerase do? What two subunits make it up?
It is an enzyme which grows telomeres and is composed of reverse transcriptase and telomerase RNA.
Do germline, embryonic and adult stem cells have telomerase?
Germline cells have telomerase and can grow telomeres.
Embryonic stem cells have telomerase and can be cultured indefinitely.
Most adult stem cells have some telomerase but usually less than germline stem cells.
What effect does accumulation of senescent cells have on stem cells?
Causes a loss of stem cells
